Low-valine diet ameliorates pathological cardiac hypertrophy by inhibiting LONP1-mediated degradation of ATP5F1B in male rodents

Branched-chain amino acids (BCAA; leucine, isoleucine, valine) are linked to cardiovascular disorders. Numerous benefits have been reported in relation to the reduced intake of dietary BCAA. Herein, a meta-analysis combined with findings from the National Health and Nutrition Examination Survey (NHANES) indicated a positive association between elevated cardiovascular risk and cumulative dietary valine intake. In hypertensive male rodents, a low-valine diet alleviates pathological cardiac hypertrophy and improves cardiac function. Mechanistically, our findings reveal that valine accumulation enhanced its binding to ATP synthase subunit beta (ATP5F1B) under hypertension, which promoted an enhanced interaction with mitochondrial ion peptidase 1 (LONP1) utilizing mass spectrometry analysis. Notably, a low-valine diet reduces the degradation of ATP5F1B mediated by LONP1, and contributes to an increase of ATP5F1B at protein levels. Thereby, it alleviates mitochondrial damage, improves mitochondrial function, and sustains mitochondrial homeostasis. These findings prove that a low-valine diet exerts cardio-protective effects in hypertensive male rodents. Restricting branched-chain amino acids is linked to metabolic benefits. Here, the authors show that valine directly binds ATP5F1B in cardiac tissue from hypertensive male rodents, and that low-valine diet stabilizes this protein by reducing LONP1-mediated degradation.